This grant application addresses the chemical synthesis problems of two architecturally complex natural products, kendomycin and garsubellin A. The broad objectives of the research program are to develop innovative strategies for the efficient synthesis of molecular agents possessing therapeutic potential for the treatment of diseases and to develop powerful chemical methods of broad utility in the production of the compounds required in biomedical investigations. The specific aims of the present proposal are: 1) the achievement of an efficient total synthesis of kendomycin, a potent endothelin receptor antagonist and calcitonin receptor agonist that exhibits pronounced antibacterial, antitumor, and anti-osteoporotic activities, using a novel macroglycosylation approach;2) the development of innovative strategies based on a mechanistically degenerative tandem approach that are appropriate for the expeditious synthesis of the core skeleton of kendomycin;3) the establishment of a chemical model to gain insights into the biosynthesis of kendomycin through a total synthesis using a biomimetic cascade approach based on novel internal redox and macro-Michael addition processes;and 4) the achievement of a concise total synthesis of garsubellin A, a potent neurotrophic agent that induces the biosynthesis of neurotransmitters, using a multicomponent tandem approach that allows for rapid assembly of the core structure of hyperforin natural products. The proposed synthetic investigations take advavantage of multicomponent cascade approaches which most efficiently address the problem of constructing complex molecular structures. Thus, the chemistry we seek to develop through this grant application can be extended in many ways to bring significant advances in the chemical synthesis of bioactive compounds.